Studies in Dementia and Neurodegenerative Diseases

痴呆症和神经退行性疾病研究

• 批准号: 8931651
• 负责人: Dimitrios Kapogiannis
• 金额: $ 21.11万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8931651
• 关键词: Age; Aging; Agonist; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animals; Atrophic; Baltimore; Biological Markers; Blood; Blood Pressure; Brain; Brain Chemistry; Butyrylcholinesterase; Caloric Restriction; Case-Control Studies; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Collaborations; Controlled Clinical Trials; Data; Dementia; Deposition; Diagnosis; Diagnostic; Disease; Disease Progression; Dose; Double-Blind Method; Drug Kinetics; Dyslipidemias; Energy Metabolism; Enrollment; Episodic memory; Event; France; Frontotemporal Dementia; Functional Magnetic Resonance Imaging; Future; Generations; Genetic; Glucose; Glutamates; Glutamine; Glycolysis; Goals; Health; Hippocampus (Brain); Human; Hypertension; Image; Immune; Individual; Inflammatory; Institutional Review Boards; Insulin Resistance; Intake; Interleukin-12; International; Journals; Lead; Link; Lipids; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manuscripts; Measures; Memory; Mentors; Metabolic; Metabolic syndrome; Metabolism; Methodology; NCAM1 gene; National Institute of Neurological Disorders and Stroke; Nature; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurology; Neurons; Neuropsychology; Neurotransmitters; Obesity; Outcome Measure; Overweight; Participant; Pathogenesis; Patient Recruitments; Patients; Pattern; Peptides; Performance; Peripheral; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Plasma; Positron-Emission Tomography; Postdoctoral Fellow; Preparation; Process; Production; Prognostic Marker; Proteins; Protocols documentation; Psychiatry; Publishing; Randomized; Reliance; Research; Research Personnel; Rest; Safety; Sampling; Sorting - Cell Movement; Specimen; Staging; Structure; Surface; Synapses; Techniques; Texas; Therapeutic; Time; Universities; Woman; Work; base; brain metabolism; brain volume; clinical Diagnosis; clinical care; cohort; cytokine; data reduction; design; disease diagnosis; disorder control; exenatide; frontal lobe; gamma-Aminobutyric Acid; genome wide association study; glucagon-like peptide; glucose metabolism; healthy volunteer; improved; in vivo; inclusion criteria; independent component analysis; inflammatory marker; inhibitor/antagonist; insulin sensitivity; interest; middle age; mild cognitive impairment; neuroimaging; neurotransmission; novel; novel therapeutic intervention; pre-clinical; receptor; symposium; systematic review; tau Proteins; treatment center

Predictors and biomarkers of Alzheimer's Disease (AD) In collaboration with Dr. Ed Goetzl from UCSF and other investigators, we developed a methodology for isolating blood exosomes and enriching them for neuronal origin by immune sorting using neuronal surface markers NCAM and L1 CAM. We conducted two case control studies measuring exosomal Ab, tau, and IRS-1 peptides and found highly significant differences between AD and control subjects that discriminate between the two groups with near 100% accuracy. In addition, exosomal differences are present at the preclinical stage and may predict AD by up to 10 years. I presented the findings at the 2014 Alzheimer's Association International Conference (AAIC), while one manuscript is in press in the journal Alzheimer's and Dementia, and a second one under review in the journal FASEB. One major goal is to validate exosomal markers as diagnostic and prognostic biomarkers of AD in large cohorts from the Baltimore Longitudinal Study of Aging (BLSA) and Alzheimer's Disease Neuroimaging Initiative (ADNI). The BLSA is ideal to assess longitudinal changes in these markers and their potential to predict AD at the preclinical stage, whereas ADNI is ideal for assessing changes with disease progression and conversion from MCI to AD. I implemented a data reduction technique called Independent Component Analysis to structural MRI images of subjects with AD and MCI from ADNI and studied how patterns of structural covariance predict clinical diagnosis and MCI conversion. This approach allowed us to classify subjects according to their future diagnosis with a high degree of accuracy (arguably, the highest ever achieved); the study is currently in press in the journal Psychiatry Research Neuroimaging. In a large cohort derived from the BLSA, I examined the performance of metabolic syndrome components (several measures of blood pressure, plasma lipids and glucose, and BMI) followed longitudinally as predictors for AD. I found that higher blood pressure, dyslipidemia and higher BMI increase possibility of AD diagnosis and their longitudinal trajectories may even be used to accurately predict future AD diagnosis with lead time of several years (the study is currently under review in the journal JAMA Neurology). In addition, I studied how peripheral insulin resistance is associated with regional brain glucose metabolism on FDG-PET in ADNI participants. We found that insulin resistance is associated with a maladaptive increase in metabolism at the hippocampus during the MCI stage, therefore, promoting AD pathogenesis; the study is currently under review in the journal Neurology. Together with Dr. Auriel Willette, a post-doctoral fellow whom I mentor, we conducted a systematic review of neuroimaging studies looking at associations of obesity and brain volume across the age-span. We found that increased obesity is associated with atrophy mainly in the frontal lobes. Our review was published by the journal Aging Research Reviews. In collaboration with the NIA 3T MRI Facility manager, Dr. David Reiter, I have employed a novel Magnetic Resonance Spectroscopy (MRS) methodology at the NIA 3T MRI facility, which allows us to obtain in vivo measures on brain metabolites (glucose, lactate) and neurotransmitters (glutamate and GABA), which are relevant to AD pathogenesis. First, I conducted a study of healthy volunteers combining MRS with resting fMRI, which provides measures of brain functional connectivity, and showed a link between neurotransmitter levels and brain connectivity. The study was pubmished in Neuroimage. In a case-control study of patients with MCI/AD and healthy volunteers, we showed higher glucose and lactate, and lower glutamate and GABA in patients compared to controls, suggesting that these MRS markers may be used as diagnostic biomarkers for AD. These findings were presented at the AAIC 2014 and the manuscript is under preparation. In addition, we are exploring associations of MRS measures with cognitive performance, functional connectivity within the default mode network; and CSF biomarkers. I also studied the association between cognitive performance and clinical status in AD and CSF inflammatory markers and found that higher levels of one particular pro-inflammatory cytokine, IL-12, predicts better cognition and clinical status; this study is currently under preparation. Finally, in collaboration with Dr. Mohamad El Haj from University of Lille, France, we conducted a study on autobiographical generation of past and future events in a cohort of AD patients compared to controls. We found that future and past events are more similar in patients compared to controls and that the ability to generate future events is closely related with the patient's episodic memory. These findings suggest that remembering the past and imagining the future rely on common brain structures, which are impaired in AD. The study is under review in the journal Neuropsychology. Treatment studies in AD I conduct a proof of concept Phase II, double blind, randomized, placebo-controlled, clinical trial to assess the safety and tolerability of exendin-4 (exenatide) treatment in participants with Mild Cognitive Impairment (MCI)/early AD. To this date, 38 participants have been enrolled, out of which 20 fulfilled inclusion criteria (clinical diagnosis of MCI/early AD, cerebrospinal fluid Ab(1-42) < 192 pg/dl) and were started on treatment with the study drug (exenatide or placebo). Participants receive study drug for 18 months and outcome measures are being collected every six months. Twelve participants completed the study, four participants withdrew from the study, and four continue participation. My goal for the new year is to reach the enrollment target of forty participants. I continue to conduct a Phase I, double-blind, placebo-controlled, ascending, single-dose, safety, tolerability and pharmacokinetic study of Bisnorcymserine, a selective butyrylcholinesterase inhibitor, in healthy volunteers. Inhibition of butyrylcholinesterase is a novel therapeutic approach for symptomatic treatment in moderate/advanced AD. Studies in Frontotemporal Dementia. As part of an ongoing collaboration with researchers at the National Institute of Neurological Disorders and Stroke and Texas Tech University, I contributed to a large GWAS study of Frontotemporal Dementia. We published our findings including identification Frontotemporal Dementia cohort in Neurobiology of Aging. In addition, I contributed to a GWAS study in FTD, which is currently under review in Nature Genetics.

阿尔茨海默病 (AD) 的预测因素和生物标志物 我们与 UCSF 的 Ed Goetzl 博士和其他研究人员合作，开发了一种分离血液外泌体并通过使用神经元表面标记物 NCAM 和 L1 CAM 进行免疫分选来富集神经元起源的方法。我们进行了两项病例对照研究，测量外泌体 Ab、tau 和 IRS-1 肽，发现 AD 和对照受试者之间存在高度显着差异，能够以接近 100% 的准确度区分两组。此外，外泌体差异在临床前阶段就已经存在，并且可以预测 AD 长达 10 年。我在 2014 年阿尔茨海默病协会国际会议 (AAIC) 上介绍了这些发现，同时一份手稿正在《阿尔茨海默病和痴呆》杂志上发表，另一份手稿正在 FASEB 杂志上审查。一个主要目标是在巴尔的摩纵向衰老研究 (BLSA) 和阿尔茨海默病神经影像计划 (ADNI) 的大型队列中验证外泌体标记物作为 AD 诊断和预后生物标记物的作用。 BLSA 非常适合评估这些标志物的纵向变化及其在临床前阶段预测 AD 的潜力，而 ADNI 非常适合评估疾病进展和从 MCI 向 AD 转化的变化。 我对来自 ADNI 的 AD 和 MCI 受试者的结构 MRI 图像实施了一种称为独立成分分析的数据缩减技术，并研究了结构协方差模式如何预测临床诊断和 MCI 转换。这种方法使我们能够根据受试者未来的诊断进行高度准确的分类（可以说是有史以来最高的准确率）；该研究目前发表在《精神病学研究神经影像学》杂志上。 在来自 BLSA 的一个大型队列中，我纵向检查了代谢综合征各组成部分（血压、血脂和血糖以及 BMI 的多项测量值）的表现，作为 AD 的预测因子。我发现较高的血压、血脂异常和较高的 BMI 会增加 AD 诊断的可能性，它们的纵向轨迹甚至可以用来准确预测未来的 AD 诊断，并且需要数年的时间（该研究目前正在 JAMA Neurology 杂志上进行审查）。 此外，我还通过 FDG-PET 研究了 ADNI 参与者的外周胰岛素抵抗与区域脑葡萄糖代谢的关系。我们发现，胰岛素抵抗与 MCI 阶段海马代谢不良增加有关，因此促进 AD 发病；该研究目前正在《神经病学》杂志上进行审查。 我们与我指导的博士后研究员 Auriel Willette 博士一起，对神经影像学研究进行了系统回顾，研究了不同年龄段肥胖与脑容量之间的关系。我们发现肥胖增加主要与额叶萎缩有关。我们的评论发表在《衰老研究评论》杂志上。 我与 NIA 3T MRI 设施经理 David Reiter 博士合作，在 NIA 3T MRI 设施中采用了一种新颖的磁共振波谱 (MRS) 方法，该方法使我们能够获得与 AD 发病机制相关的脑代谢物（葡萄糖、乳酸）和神经递质（谷氨酸和 GABA）的体内测量结果。首先，我对健康志愿者进行了一项研究，将 MRS 与静息功能磁共振成像相结合，提供大脑功能连接的测量，并显示神经递质水平和大脑连接之间的联系。该研究发表在《神经影像》杂志上。在一项针对 MCI/AD 患者和健康志愿者的病例对照研究中，我们发现与对照组相比，患者的葡萄糖和乳酸较高，而谷氨酸和 GABA 较低，这表明这些 MRS 标记物可用作 AD 的诊断生物标记物。这些发现已在 AAIC 2014 上发表，手稿正在准备中。此外，我们正在探索 MRS 测量与默认模式网络内的认知表现、功能连接的关联；和脑脊液生物标志物。 我还研究了 AD 和 CSF 炎症标志物中认知表现与临床状态之间的关联，发现一种特定促炎细胞因子 IL-12 水平较高，可预测更好的认知和临床状态；这项研究目前正在准备中。 最后，我们与法国里尔大学的 Mohamad El Haj 博士合作，对一组 AD 患者与对照组的过去和未来事件的自传体生成进行了研究。我们发现，与对照组相比，患者未来和过去的事件更加相似，并且产生未来事件的能力与患者的情景记忆密切相关。这些发现表明，记住过去和想象未来依赖于常见的大脑结构，而这些结构在 AD 中受损。该研究正在《神经心理学》杂志上进行审查。 AD 治疗研究 我进行了一项概念验证 II 期、双盲、随机、安慰剂对照临床试验，以评估 exendin-4（艾塞那肽）治疗轻度认知障碍 (MCI)/早期 AD 参与者的安全性和耐受性。迄今为止，已有 38 名参与者入组，其中 20 名符合纳入标准（MCI/早期 AD 的临床诊断，脑脊液抗体 (1-42) < 192 pg/dl），并开始接受研究药物（艾塞那肽或安慰剂）治疗。参与者接受研究药物 18 个月，每六个月收集一次结果测量结果。十二名参与者完成了研究，四名参与者退出了研究，四名参与者继续参与。我新的一年的目标是达到四十名学员的报名目标。 我继续在健康志愿者中进行双去甲丝氨酸（一种选择性丁酰胆碱酯酶抑制剂）的 I 期、双盲、安慰剂对照、升序、单剂量、安全性、耐受性和药代动力学研究。丁酰胆碱酯酶的抑制是中度/晚期 AD 对症治疗的一种新型治疗方法。 额颞叶痴呆研究。 作为与国家神经疾病和中风研究所以及德克萨斯理工大学研究人员持续合作的一部分，我为额颞叶痴呆的大型 GWAS 研究做出了贡献。我们在衰老神经生物学中发表了我们的研究结果，包括识别额颞叶痴呆队列。此外，我还参与了 FTD 的 GWAS 研究，该研究目前正在《自然遗传学》杂志上进行审查。